The effectiveness of treatment for hyperproliferative disorders, (e.g., malignant and benign tumors), with chemotherapeutic drugs is limited by several significant barriers, including: i) nonspecific toxicity of the drugs for normal as well as tumor tissues; ii) inefficiency of drug delivery to target cells; and iii) inappropriate release of the drug. Consequently, many chemotherapeutic drugs are characterized as having low therapeutic indexes, and thus, relatively high doses of the drugs are required, which, in turn, results in serious side effects. As such, the development of additional targeted delivery systems for the delivery of chemotherapeutic drugs to target cells would resolve many of the undesirable aspects of chemotherapy. This invention addresses that need by targeting drugs to cells that express abnormally high levels of the plasma cell membrane components of the system xc− heterodimeric amino acid transporter specific for cystine/glutamate exchange.
System xc− imports L-cystine into the intracellular compartment of a cell, which requires L-cystine for the synthesis of glutathione (L-γ-glutamyl-L-cysteinylglycine, referred to herein as “GSH”), an antioxidant that is important for cell survival under hypoxic conditions, such as those that exist in a tumor environment. The structure of System xc− imports is composed of SLC7A11, a catalytic subunit that gives the transporter its specificity for cystine, and SLC3A2, a regulatory subunit. SLC7A11 and SLC3A2 are also known in the field as xCT and 4F2hc/CD98, respectively.
Because tumor cells, and other abnormally rapidly dividing or differentiating cells require greater amounts of GSH to handle higher levels of oxidative stress, such cells more highly express system xc− components for the importation of cystine than do normal cells under normal conditions. As such, the invention takes advantage of the increased expression of system xc− components by hyperproliferative cells by providing drug and diagnostic delivery vehicles that incorporate cystine to mediate the delivery vehicles to the system xc− components of target cells.